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Signal enhancement of magnetic resonance imaging (MRI) in the diseased region is dependent on the molecular structure of the MRI contrast agent. In this study, a macromolecular contrast agent, Branched-LAMA-DOTA-Cy5.5-Gd (BLDCGd), was prepared to target liver cancer. Due to the affinity of lactose to the Asialoglycoprotein receptor (ASGPR) over-expressed on the surface of liver cancer cells, lactose was selected as the targeting moiety in the contrast agent. A cathepsin B-sensitive tetrapeptide, GFLG, was used as a linkage moiety to construct a cross-linked macromolecular structure of the contrast agent, and the contrast agent could be degraded into fragments for clearance. A small-molecular-weight molecule, DOTA-Gd, and a fluorescent dye, Cy5.5, were conjugated to the macromolecular structure

Targeting metabolic vulnerability of tumor cells is a promising anti-cancer strategy. However, the therapeutic efficacy of existing metabolism-regulating agents is often compromised due to tolerance resulting from tumor metabolic plasticity, as well as their poor bioavailability and tumor-targetability. Inspired by the inhibitive effect of N-ethylmaleimide on the mitochondrial function, we developed a dendronized polymer-functionalized metal-phenolic nanomedicine (pOEG-b-D-SH@NP) encapsulating N-ethylmaleimide-modified doxorubicin (Mal-DOX) to enable improvement in the overall delivery efficiency and inhibition of the tumor metabolism via multiple pathways. We observe that Mal-DOX and its derived nanomedicine induce energy depletion of CT26 colorectal cancer cells more efficiently than doxorubicin, and shifts the balance of programmed cell death from apoptosis toward necroptosis. Notably, pOEG-b-D-SH@NP simultaneously inhibits cellular oxidative phosphorylation and glycolysis, thus potently suppressing cancer growth and peritoneal intestinal metastasis in mouse models. Overall, the study provides a promising dendronized polymer-derived nano-platform for the treatment of cancers through impairing metabolic plasticity. This article is protected by copyright. All rights reserved.

Interaction between carcinoma-associated fibroblasts (CAFs) and tumor cells leads to the invasion and metastasis of breast cancer. Herein, we prepared a redox-responsive chondroitin sulfate (CS)-based nanomedicine, in which hydrophobic cabazitaxel (CTX) was conjugated to the backbone of CS via glutathione (GSH)-sensitive dithiomaleimide (DTM) to form an amphipathic CS-DTM-CTX (CDC) conjugate, and dasatinib (DAS) co-assembled with the CDC conjugate to obtain DAS@CDC. After CD44 receptor-mediated internalization by CAFs, the nanomedicine could reverse CAFs to normal fibroblasts, blocking their crosstalk with tumor cells and reducing synthesis of major tumor extracellular matrix proteins, including collagen and fibronectin. Meanwhile, the nanomedicine internalized by tumor cells could effectively inhibit tumor proliferation and metastasis, leading to shrinkage of the tumor volume and inhibition of lung metastasis in a subcutaneous 4T1 tumor model with low side effects. Collectively, the nanomedicine showed a remarkably synergistic therapy effect against breast cancer by modulating tumor-stromal crosstalk.

Tumor cells are dominant in the nutritional competition in the tumor microenvironment (TME), and their metabolic abnormalities often lead to microenvironmental acidosis and nutrient deprivation, thereby impairing the function of immune cells and diminishing the anti-tumor therapeutic effect. Herein, we report a branched polymeric conjugate and its efficacy in attenuating the metabolic competition of tumor cells. Compared with the control nanoparticles prepared from its linear counterpart, the branched conjugate-based nanoparticles (branched NPs) could more efficiently accumulate in the tumor tissue and interfere with the metabolic processes of tumor cells to increase the concentration of essential nutrients and reduce the level of immunosuppressive metabolites in the TME, thus creating a favorable environment for infiltrated immune cells. Its combined treatment with an immune checkpoint inhibitor (ICI) achieved an enhanced anti-tumor effect. Our work presents a promising approach for targeting the metabolic competition in the TME to enhance the chemo-immunotherapeutic effect against cancers. This article is protected by copyright. All rights reserved.

Histones are the alkali proteins in eukaryotic somatic chromatin cells which constitute the nucleosome structure together with DNA. Their abnormality is often associated with multiple tumorigenesis and other human diseases. Nevertheless, a simple and efficient super-resolution method to visualize histone distribution at the subcellular level is still unavailable. Herein, a Zn(II) terpyridine complex with rich-electronic azide units, namely, TpZnA-His, was designed and synthesized. The initial in vitro and in silico studies suggested that this complex is able to detect histones rapidly and selectively via charge-charge interactions with the histone H3 subunit. Its live cell nuclear localization, red-emission tail, and large Stokes shift allowed super-resolution evaluation of histone distributions with a clear distinction against nuclear DNA. We were able to quantitatively conclude three histone morphology alternations in live cells including condensation, aggregation, and cavity during activating histone acetylation. This work offers a better understanding as well as a versatile tool to study histone-involved gene transcription, signal transduction, and differentiation in cells.

Dendron-polymer-based nanoscale and stimuli-responsive drug delivery systems have shown great promise in tumor-targeting accumulation without significant toxicity. Here we report a dendronized polymer-doxorubicin (DOX) hybrid (DPDH) with an improved in vivo drug delivery efficiency for cancer therapy compared with a linear polymer-DOX conjugate (LPDC). The in vitro drug release profile of DOX indicates that DPDH displays pH-responsive drug release due to cleavage of hydrazone bonds since a greater amount of DOX is released at pH 5.2 at a faster rate than at pH 7.4. DPDH efficiently enters 4T1 cells and releases DOX to induce cytotoxicity and apoptosis. Owing to the dendronzied structure, DPDH has a significantly longer blood circulation time than LPDC. DPDH substantially enhances the therapeutic efficacy to suppress tumor growth in a 4T1 mammary cancer model than LPDC as well as free drug, evidenced from tumor growth inhibition, TUNEL assessment and histological analysis. Biosafety of DPDH is also confirmed from hemolysis, body weight shifts during treatment and pathological analysis. This study demonstrates the use of dendronized polymer-DOX hybrids for specific drug molecules is a promising approach for drug delivery.

Combination therapy is a promising approach for effective treatment of tumors through synergistically regulating pathways. However, the synergistic effect is limited, likely by uncontrolled co-delivery of different therapeutic payloads in a single nanoparticle. Herein, a combination nanotherapeutic is developed by using two amphiphilic conjugates, hyperbranched poly(ethylene glycol)-pyropheophorbide-a (Ppa) (HP-P) and hyperbranched poly(ethylene glycol)-doxorubicin (DOX) (HP-D) to construct co-assembly nanoparticles (HP-PD NPs) for controllably co-loading and co-delivering Ppa and DOX. In vitro and in vivo antitumor studies confirm the synergistic effect of photodynamic therapy and chemotherapy from HP-PD NPs. Metabolic variations reveal that tumor suppression is associated with disruption of metabolic homeostasis, leading to reduced protein translation. This study uncovers the manipulation of metabolic changes in tumor cells through disruption of cellular homeostasis using HP-PD NPs and provides a new insight into the rational design of synergistic nanotherapeutics for combination therapy.

Linear-dendritic block copolymer (LDBCs) are highly attractive candidates for smart drug delivery vehicles. Herein, we report an amphiphilic poly[(ethylene glycol) methyl ether methacrylate] (POEGMA) linear-peptide dendritic prodrug of doxorubicin (DOX) prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization. A hydrophobic dye-based photosensitizer chlorin e6 (Ce6) was employed for encapsulation in the prodrug nanoparticles (NPs) to obtain a LDBCs-based drug delivery system (LD-DOX/Ce6) which offered a combination cancer therapy. Due to the presence of Gly-Phe-Leu-Gly peptides and hydrazone bonds in the prodrug structure, LD-DOX/Ce6 were degraded into small fragments, thus specifically triggering the intracellular release of DOX and Ce6 in the tumor microenvironment. Bioinformatics analysis suggested that LD-DOX/Ce6 with laser irradiation treatment significantly induced apoptosis, DNA damage and cell cycle arrest. The combination treatment could not only suppress tumor growth, but also significantly reduced tumor metastasis compared with treatments with DOX or Ce6 through regulating EMT pathway, TGFβ pathway, angiogenesis and the hypoxia pathway. LD-DOX/Ce6 displayed a synergistic chemo-photodynamic anti-tumor efficacy, resulting in a high inhibition in tumor growth and metastasis, while maintaining an excellent biosafety. Therefore, this study has demonstrated potential of the biodegradable and tumor microenvironment-responsive LDBCs as an intelligent multifunctional drug delivery vehicle for high-efficiency cancer combination therapy. This article is protected by copyright. All rights reserved.

Nanoparticles (NPs)-based cancer therapeutics is generally impeded by poor drug penetration into solid tumors due to their dense tumor extracellular matrix (ECM). Herein, we develop pH/redox-responsive dendritic polymer-based NPs to amplify the neighboring effect for improving drug penetration and driving cell apoptosis via combination therapy. Pyropheophorbide a (Ppa) is conjugated with PEGylated dendritic peptides via disulfide bonds and doxorubicin (DOX) encapsulated in the conjugate to construct dual-responsive NPs, PDPP@D. Delayed released DOX and Ppa from PDPP@D exert their combination therapeutic effect to induce cell apoptosis, and then they are liberated out of dying cells to amplify the neighboring effect, resulting in their diffusion through the dense ECM and penetration into solid tumors. Transcriptome studies reveal that PDPP@D leads to irreversible stress on the endoplasmic reticulum and inhibits cell protection through blocking the IRE1-dependent survival pathway and unleashing the DR5-mediated caspase activity to promote cell death. The strategy of amplifying the neighboring effect of NPs through combination therapy may offer great potential in enhancing drug penetration and eradicating solid tumors. This article is protected by copyright. All rights reserved.

Efficient penetration and retention of therapeutic agents in tumor tissues can be realized through rational design of drug delivery systems. Herein, we present a polymer-dendron conjugate, POEGMA-b-p(GFLG-Dendron-Ppa) (GFLG-DP), which allows cathepsin B (CTSB)-triggered stealthy-to-sticky structural transformation. The compositions and ratios were optimized through dissipative particle dynamics simulations. GFLG-DP displayed tumor-specific transformation and consequently released dendron-Ppa was found to effectively accumulate on the tumor cell membrane. The interaction between dendron-Ppa and the tumor cell membrane resulted in intracellular and intercellular transport via membrane flow, thus achieving efficient deep penetration and prolonged retention of therapeutic agents in solid tumor tissues. Meanwhile, the interaction of dendron-Ppa with endoplasmic reticulum disrupted the cell homeostasis, making tumor cells more vulnerable and susceptible to the photodynamic therapy. This platform represents a versatile approach to augmenting the tumor therapeutic efficacy of a nanomedicine via manipulation of its interactions with tumor membrane systems. This article is protected by copyright. All rights reserved.

To deliver photosensitizers with PEGylated heparin (HP) into tumor cells for photodynamic therapy, we prepared two polyethylene glycol (PEG)-functionalized HP-based polymers conjugated with pyropheophorbide-a (Ppa): a non-GSH-responsive nanoagent (HP-Ppa-mPEG) with the mPEG moiety chemically attached to HP directly; and a GSH-responsive nanoagent (HP-Ppa-SS-mPEG) with the mPEG moiety conjugated to HP via a disulfide linkage. The Ppa-functionalized HP without PEGylation (HP-Ppa) was designed as another control. These amphiphilic polymers could aggregate into nanoparticles. Cellular uptake of three nanoparticles by 4T1 cells led to abundant production of reactive oxygen species after irradiation by a 660 nm laser, inducing cell apoptosis. HP-Ppa-SS-mPEG was found to achieve the highest tumor accumulation, the longest retention time and the best penetration into tumor tissues, resulting in the highest in vivo anticancer efficacy with 94.3 % tumor growth inhibition rate, suggesting that tumor microenvironment-responsive PEGylated HP-based nanomedicines may act as efficient anticancer agents.

To enhance the drug delivery efficiency of hyaluronic acid (HA), we designed and prepared glycodendron and pyropheophorbide-a (Ppa)-functionalized HA (HA-Ppa-Dendron) as a nanosystem for cancer photodynamic therapy. Linear Ppa-modified HA (HA-Ppa) was also prepared as a control. Cellular uptake of both polymers by MDA-MB-231 cells led to mitochondrial dysfunction and generation of reactive oxygen species under the irradiation of a laser. Compared to the linear polymer, HA-Ppa-Dendron had higher molecular weight, a more compact nanoscale particle size, and a dendritic structure, resulting in a much longer blood circulation time and higher tumor accumulation. HA-Ppa-Dendron outperformed HA-Ppa in inhibiting cell growth, with 60 % of tumors was eradicated under laser irradiation. Tumor growth inhibition (TGI) up to 99.2 % was achieved from HA-Ppa-Dendron, which was much higher than that of HA-Ppa (50.6 %). Therefore, glycodendron-functionalized HAs by integration of HA and dendritic polymers may act as efficient anti-cancer nanomedicine.

In this study, we designed and fabricated a novel amphiphilic biodegradable triblock N-(2-hydroxypropyl methyl) acrylamide (HPMA) copolymer-gadolinium- paclitaxel-Cyanine5.5 (pHPMA-Gd-PTX-Cy5.5) conjugate and further studied its theranostic nanomedicine for cancer treatment. The amphiphilic block polymer was synthesized through two-step RAFT polymerization, and self-assembled into a nanoparticle with a diameter of around 85 nm. The enzyme-sensitive tetrapeptide GFLG linker was introduced to the backbone of the polymer as a spacer to conjugate the anticancer drug paclitaxel (PTX) to the polymeric carrier, allowing the conjugate with a high molecular weight (MW, 92 kDa) to degrade into low MW products (44 kDa), as well as to release the drug in the cancer microenvironment. The Cy5.5 and Gd(III)-labeled nanoparticles had 5 folds T1 relaxivity relative to the clinical magnetic resonance imaging (MRI) contrast agent Gd-DTPA, enhancing the imaging capacity of the theranostic nanomedicine. In vivo MR imaging, fluorescence imaging and Gd(III) histological distribution demonstrated that the residence time of the multifunctional conjugate-based nanoparticles has been significantly prolonged and accumulation of the conjugate at the tumor site has been increased. The conjugate-based nanoparticles therefore significantly inhibited proliferation and induced apoptosis of the 4T1 murine breast cancer cells in the xenograft tumor model and no obvious side effects were observed. Overall, the theranostic nanomedicine derived from the enzyme-sensitive biodegradable pHPMA-Gd-PTX-Cy5.5 conjugate may open a door for simultaneous therapeutic treatment and MR imaging of breast cancer.

Supramolecular self‐assemblies of dendritic peptides with well‐organized nanostructures have great potential as multifunctional biomaterials, yet the complex self‐assembly mechanism hampers their wide exploration. Herein, a self‐stabilized supramolecular assembly (SSA) constructed from a PEGylated dendritic peptide conjugate (PEG‐dendritic peptide‐pyropheophorbide a, PDPP), for augmenting tumor retention and therapy, is reported. The supramolecular self‐assembly process of PDPP is concentration‐dependent with multiple morphologies. By tailoring the concentration of PDPP, the supramolecular self‐assembly is driven by noncovalent interactions to form a variety of SSAs (unimolecular micelles, oligomeric aggregates, and multi‐aggregates) with different sizes from nanometer to micrometer. SSAs at 100 nm with a spherical shape possess extremely high stability to prolong blood circulation about 4.8‐fold higher than pyropheophorbide a (Ppa), and enhance tumor retention about eight‐fold higher than Ppa on day 5 after injection, which leads to greatly boosting the in vivo photodynamic therapeutic efficiency. RNA‐seq demonstrates that these effects of SSAs are related to the inhibition of MET‐PI3K‐Akt pathway. Overall, the supramolecular self‐assembly mechanism for the synthetic PEGylated dendritic peptide conjugate sheds new light on the development of supramolecular assemblies for tumor therapy., A self‐stabilized supramolecular assembly (SSA) from the PEGylated dendritic peptide conjugate is presented, which builds on the concentration‐dependent supramolecular self‐assembly that demonstrates ultrahigh colloidal stability and enhanced tumor retention to boost its photodynamic therapeutic efficiency. This study reveals the supramolecular self‐assembly mechanism of SSAs and further expands the advanced functions of dendritic peptides in the field of cancer therapy.

To achieve target delivery of anti-tumor drugs with great biocompatibility into tumor tissues, a stimuli-responsive dendronized hyaluronic acid (HA)-docetaxel conjugate (HA-DTX-Dendron, HADD) was designed and prepared. The incorporation of HA in HADD improved the delivery of DTX to tumor cells with rich CD44 receptors. Enhanced biocompatibility and therapeutic outcomes were achieved using glyodendrons-modified HA and tumor microenvironment-responsive linkers in HADD. The glycodendron was connected with HA via GSH-responsive disulfide bonds, and the drug DTX was linked to the carrier via a cathepsin B-responsive tetrapeptide GFLG. This design resulted in self-assembly nanostructures for facilitating uptake of HADD by tumor cells and rapid release of DTX to exert its therapeutic effect. Compared to free DTX, HADD showed much higher tumor growth inhibition in the MDA-MB-231 tumor-bearing mice model (up to 99.71%), and no toxicity was observed. Therefore, HADD could be employed as an efficacious nano-agent for treating triple negative breast cancer (TNBC).

Stimuli-responsive peptide dendrimer-drug conjugates have presented significant potential for cancer therapy. To develop an effective nanoscale chemotherapeutic prodrug, we developed a novel enzyme-responsive PEGylated lysine peptide dendrimer-gemcitabine conjugate (Dendrimer-GEM) based nanoparticle via the highly efficient click reaction. Owing to the glycyl phenylalanyl leucyl glycine tetra-peptide (GFLG) as an enzyme-cleavable linker to conjugate gemcitabine (GEM), the prepared nanoparticles were able to release drug significantly faster in the tumor cellular environments, which specifically contains secreted Cathepsin B, quantifiably more than 80% GEM was released with Cathepsin B compared to the condition without Cathepsin B at 24h. This nanoparticle demonstrated enhanced antitumor efficacy in a 4T1 murine breast cancer model without obvious systemic toxicity, resulting in significantly suppressed relative tumor volumes (86.17±38.27%) and a 2-fold higher value of tumor growth inhibition (∼90%) than GEM·HCl treatment. These results suggest that the PEGylated peptide dendrimer-gemcitabine conjugate can be an effective antitumor agent for breast cancer therapy. Statement of Significance We found that the functionalized dendrimer based nanoscale drug delivery vehicles exhibited enhanced therapeutic indexes and reduced toxicity as compared to the free drug gemcitabine. Compared with current nanoparticles, such as dendritic anticancer drug delivery systems, the new design was capable of self-assembling into nanoscale particles with sizes of about 80-110nm, which is suitable as antitumor drug delivery vehicle due to the potential longer intravascular half-life and higher accumulation in tumor tissue via EPR effect. Owing to the optimized architecture, the system was given the enzyme-responsive drug release feature, and showed excellent antitumor activity on the 4T1 breast tumor model due to the evidences from tumor growth curves, immunohistochemical analysis and confocal laser scanning microscopy. Meanwhile, no significant side effect was observed by histological analysis. This study demonstrated that PEGylated peptide dendritic architecture may be used as efficient and safe nanoscale drug delivery vehicle for cancer therapy.

Hydrophile-lipophile balance (HLB) has a great influence on the self-assembly and physicochemical properties of amphiphiles, thus affecting their biological effects. It is shown that amphiphilic nanoparticles (NPs) with a moderate HLB value display enhanced stability and highly efficient tumor retention. 2,2-Bis(hydroxymethyl)propionic acid hyperbranched poly(ethylene glycol) (PEG)-pyropheophorbide-a (Ppa) amphiphiles (G320P, G310P, G220P, and G210P) are synthesized with a tunable HLB value from 6.1 to 9.9 by manipulating the number of generation of dendrons (G2 or G3) and the molecular weight of PEG chains (10 or 20 kDa). Molecular dynamics simulations reveal that G320P and G210P with a moderate HLB value (8.0 and 7.8) self-assemble into very stable NPs with a small solvent accessible surface area and high nonbonding interactions. G320P with a moderate HLB value (8.0) and a long PEG chain excels against other NPs in prolonging the blood circulation time of Ppa (up to 13-fold), penetrating deeply into multicellular tumor spheroids and accumulating in tumors, and enhancing the PDT efficacy with a tumor growth inhibition of 96.0%. Rational design of NPs with a moderate HLB value may be implemented in these NP-derived nanomedicines to achieve high levels of retention in tumors.

Photodynamic therapy (PDT) has shown its promise in the treatment of cancer. Herein, a dendron-functionalized polyglutamic acid (PGA) polymer (PG-L8G-Ppa-Dendron, PGPD) is synthesized and it is conjugated with pyropheophorbide-a (Ppa) for the first time to treat triple negative breast cancer (TNBC), whereas a linear polyglutamate-Ppa conjugate (PGP) is synthesized as a control. Compared to the linear counterpart, the glycosylated polymer-based PGPD with a dendritic structure has excellent solubility and it self-assembles to form uniform-sized nanoparticles. PGPD displays a highly effective PDT effect in the animal model, evidenced with effective induction of reactive oxygen species (ROS) production and cell apoptosis. This may be due to an enhanced efficiency in delivery and accumulation of Ppa by this glycosylated dendritic polymer at tumor sites. Therefore, PGPD can be a highly effective and biosafe nanoagent for PDT of TNBC.

In this study, we designed and fabricated a nanohybrid of mesoporous silica nanoparticles (MSNs) functionalized with peptide dendrons and evaluated its potential biocompatibility. The nanohybrid was prepared by combining azido-MSNs with alkynyl peptide dendrons via click chemistry to improve graft ratio. By modifying the azido-MSNs through the addition of the alkynyl peptide dendrons, we amplified and broadened the scope of their applications. After labeling with Cy5.5 dye, the nanohybrid was characterized by transmission electron microscopy (TEM), thermogravimetric analysis (TGA), nitrogen adsorption-desorption isotherms, dynamic light scattering (DLS) and zeta potential. The resulting nanohybrid showed high mono-dispersivity with a spherical diameter of 60 nm, negative surface charge and aqueous environment stability. Finally, a systematic assessment was conducted to evaluate the biocompatibility of the MSN-dendron-Cy5.5-based nanohybrid, both in vitro and in vivo. Cytotoxicity measurements, body weight shifts, histological analysis, and routine blood tests with mice demonstrated that the nanohybrid had good biocompatibility. Hemocompatibility evaluations demonstrated that the nanohybrid had improved blood safety compared to bare MSNs. Healthy nude mice were used to analyze the in vivo optical fluorescence images. Ex vivo fluorescence images of the major organs were studied to further evaluate the in vivo biodistribution of the nanohybrid, with results suggesting that the MSN-dendron-Cy5.5-based nanohybrid provided promise in biomedical applications. Overall, we provided a preliminary but important research piece on the safety and efficiency of MSN-dendron-Cy5.5-based nanohybrid as an in vivo functional vehicle used in diagnosis and therapy.

In this study, an MSN–dendron–Gd conjugate based nanoprobe was synthesized using an easy and efficient method with high purity and the nanoprobe was studied for its efficiency in contrast imaging applications. The nanoprobe was synthesized using the Cu(I)-catalyzed azide–alkyne based method, which overcame the challenges of stereospecific blockade of mesoporous silica nanohybrid synthesis. Moreover, the nanoprobe showed an approximately 11-fold increase in the relaxivity (from 5.55 mM−1 s−1 to 60.56 mM−1 s−1) and enhancement of MR images. The higher relaxivity rates were obtained via the properties of the nanoprobe contributing to an increase in the rotational correlation time, thereby increasing relaxivity. In addition, the nanoprobe displayed excellent biosafety as confirmed by in vitro and in vivo toxicity tests. Overall, the nanoprobe displayed great potential for biomedical use as a MRI contrast agent.

Metabolic demand of cancer is quite unique compared to normal tissues and this is an emerging hallmark of cancer, which brings a potential opportunity to discover drugs that target cancer cell metabolism. Herein, the development of a dendronized pyropheophorbide a (Ppa)-conjugated polymer (DPP) is reported, and a linear Ppa-conjugated polymer (LPP) is reported as a control. DPP is found to disturb cellular metabolism including increased energy depletion, dysfunctional H+ regulation, and decreased antioxidation, resulting in deficiency in protecting cells from stresses. These vulnerable cells are subjected to photodynamic therapy (PDT) treatment in the presence of DPP, resulting in attenuated cancer cell growth and eventually cell death. The in vivo anticancer efficacy is also ascribed to significantly prolonged blood circulation and enhanced tumor accumulation of DPP due to its unique molecular structure. This study presents a new platform using dendronized polymers for tumor suppression by targeting cancer cell metabolism.

Owing to the low efficacy of clinically used small-molecule gadolinium (Gd)-based magnetic resonance imaging (MRI) agents, we designed and explored biodegradable macromolecular conjugates as MRI contrast agents. The linear polymeric structure and core-cross-linked formulation possessed different characteristics and features, so we prepared and comparatively studied the two kinds of Gd-based N-(2-hydroxypropyl) methacrylamide (HPMA) polymeric systems (the core-cross-linked pHPMA-DOTA-Gd and the linear one) using the clinical agent diethylene-triamine pentaacetic acid-Gd(III) (DTPA-Gd) as a control. This study was aimed to find the optimal polymeric formulation as a biocompatible and efficient MRI contrast agent. The high molecular weight (MW, 181 kDa) and core-cross-linked copolymer was obtained via the cross-linked block linear copolymer and could be degraded to low-MW segments (29 kDa) in the presence of glutathione (GSH) and cleaned from the body. Both core-cross-linked and linear pHPMA-DOTA-Gd copolymers displayed 2-3-fold increased relaxivity (r1 value) than that of DTPA-Gd. Animal studies demonstrated that two kinds of macromolecular systems led to much longer blood circulation time, higher tumor accumulation, and much higher signal intensity compared with the linear and clinical ones. Finally, in vivo and in vitro toxicity studies indicated that the two macromolecular agents had great biocompatibility. Therefore, we performed preliminary but important studies on the Gd-based HPMA polymeric systems as biocompatible and efficient MRI contrast agents and found that the biodegradable core-cross-linked pHPMA-DOTA-Gd copolymer might have greater benefits for the foreground.

To achieve liver-specific delivery of antitumor drug doxorubicin (DOX), PEGylated dendrimer-DOX conjugates were designed and synthesized, whereas DOX was conjugated to dendrimers via hydrazone bonds and the dendrimers were functionalized with galactose moieties. The release rates of DOX from the conjugates at pH 5.0 were much faster than those at pH 7.4 due to the pH-sensitive cleavage of the hydrazone bonds. The conjugates were shown to effectively kill HepG2 cells in vitro. Compared to other conjugates, the PEGylated dendrimer-DOX one with multiple galactose moieties (Dendrimer-DOX-PEG-Gal) demonstrated HepG2 cells specificity, higher efficacy and good biosafety due to the lower IC50 value and higher cellular uptake confirmed by in vitro cytotoxicity assays, confocal laser scanning microscopy and flow cytometric studies. These results suggest that Dendrimer-DOX-PEG-Gal is an efficient and biocompatible candidate for the specific delivery of antitumor drug to HepG2 cells and could be used as liver cancer specific drug delivery system.

Mesoporous silica nanoparticles (MSNs) have been extensively studied and proposed as promising candidates for numerous biomedical applications. In this study, we report the design, preparation, characterization and biosafety evaluation of peptide dendron functionalized mesoporous silica nanohybrid. This nanohybrid was prepared by surface modification of MSNs via click reaction of azido-MSNs with alkynyl peptide dendrons, and characterized by TEM, SEM, TGA, dynamic light scattering (DLS). In vitro cytotoxicity of the nanohybrid was evaluated against different cell lines by CCK-8 assay. The in vivo toxicity evaluation was measured by body weight shift, blood routine test and histological analysis, suggesting that the peptide functionalized nanohybrid possessed good biocompatibility due to the non-observed significant side effects to normal organs of healthy mice. Overall, considering our results we believe that the peptide dendron functionalized mesoporous silica nanohybrid is very promising in further biomedical applications.

Peptide dendrimer-based nanoparticles have presented significant potential as candidates for drug delivery system. In this study, we synthesized and characterized enzyme-responsive mPEGylated peptide dendrimer–GFLG–doxorubicin conjugate (dendrimer–GFLG–DOX) as a chemotherapeutic drug delivery nano-carrier via a two-step highly efficient copper-catalyzed alkyne–azide click cycloaddition (CuAAC) reaction. The tetra-peptide sequence Gly–Phe–Leu–Gly (GFLG) was explored as an enzyme-responsive linker to connect the doxorubicin (DOX) to the periphery of mPEGylated peptide dendrimer. The dendrimer–GFLG–DOX was capable of self-assembling into nanoparticle, which was proven by dynamic light scattering (DLS) and transmission electron microscopy (TEM) studies. Compared to the free drug DOX, the dendrimer–GFLG–DOX conjugate based nanoparticle demonstrated higher accumulation and retention within SKOV-3 ovarian tumor tissue, resulting in a higher antitumor activity as evidenced from tumor growth curves, tumor growth inhibition analysis, immunohistochemical assessment and in vivo imaging. Moreover, no obvious systemic toxicity was observed via histological assessment. Thus, the mPEGylated peptide dendrimer–DOX conjugate-based nanoparticle may be a promising candidate as a nanoscale and enzyme-sensitive drug delivery vehicle for ovarian cancer therapy.

Smart liposomes that are responsive to the microenvironment of tumor tissue have been utilized to enhance chemotherapeutic efficiency. Here, we reported a novel liposome called Trojan horse liposome, which has a pH response, to enhance drug accumulation in tumor sites and intercellular uptake. L-lysine was used as a linker to connect 2,3-dimethylmaleic anhydride (DMA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE) to yield a DSPE-Lys-DMA (DLD) lipid. The pH-responsive DLD was mixed with other commercially available lipids to form liposomes. The size, morphology and zeta potential of the DLD liposomes (DLD-Lip) were measured. Paclitaxel (PTX) was loaded in the liposomes. The release profile, cellular uptake, in vitro and in vivo anticancer activity of the PTX-loaded liposomes were investigated. The results showed that the mean diameter of the liposomes was less than 200 nm. The zeta potential of the liposomes was negative at pH 7.4. However, it was transferred to positive at weak acidic pH values with the cleavage of DMA amide. The charge reversion of DMA in acidic environments facilitated the cellular internalization and endosome escape of DLD-Lip, which inhibited the proliferation of 4T1 cancer cells in vitro. The pH-responsive "Trojan horse"-like liposomes also exhibited efficient anticancer activity in the xenograft breast cancer model in vivo.

Environmentally responsive peptide dendrimers loaded with drugs are suitable candidates for cancer therapy. In this study, we report the preparation and characterization of mPEGylated peptide dendrimer-linked diaminocyclohexyl platinum (II) (dendrimer-DACHPt) conjugates as pH-responsive drug delivery vehicles for tumor suppression in mice. The DACHPt has a molecular structure, is and activity closely related to oxaliplatin and was linked to dendrimer via N,O-chelate coordination. The products were pH-responsive and released drug significantly faster in acidic environments (pH 5.0) than pH 7.4. Consequently, the conjugates suppressed tumor growth better than clinical oxaliplatin(®) without inducing toxicity in an SKOV-3 human ovarian cancer xenograft. Through the systemic delivery of conjugates, 25-fold higher tumor platinum uptake at 36 h post-injection was seen observed due to the enhanced permeability and retention (EPR) effect thereby remarkably enhancing the therapeutic indexes of this small-molecule drug. Thus, the mPEGylated peptide dendrimer-linked DACH-platinum conjugates are novel potential drug delivery systems with implications in future ovarian cancer therapy.

Peptide dendrimer drug conjugate based nanoparticles are recently developed as a potential candidate for drug delivery vehicle. In this study, we prepared and characterized the enzyme-sensitive amphiphilc mPEGylated dendron-GFLG-DOX conjugate via two-step highly efficient click reaction. Dynamic light scattering (DLS) and transmission electron microscope (TEM) studies demonstrated the mPEGylated dendron-GFLG-DOX conjugate self-assembled into compact nanoparticles with negatively charged surface. The nanoparticles with 9.62 wt% (weight percent) of DOX showed enzyme-sensitive property by drug release tests. The nanoparticles were shown to effectively kill cancer cells in vitro. The fluorescent image indicated that the nanoparticles could accumulate and retain within tumor for a long time. Moreover, the nanoparticles substantially enhanced antitumor efficacy compared to the free DOX, exhibiting much higher effects on inhibiting proliferation and inducing apoptosis of the 4T1 murine breast cancer model confirmed as the evidences from tumor growth curves, tumor growth inhibition (TGI), immunohistochemical analysis and histological assessment. The nanoparticles reduced DOX-induced toxicities and presented no significant side effects to normal organs of both tumor bearing and healthy mice as measured by body weight shifts and histological analysis. Therefore, the mPEGylated dendron-GFLG-DOX conjugate based nanoparticle serves as a potential drug delivery vehicle for breast cancer therapy.

Peptide dendrimers have shown promise as an attractive platform for drug delivery. In this study, mPEGylated peptide dendrimer-doxorubicin (dendrimer-DOX) conjugate-based nanoparticle is prepared and characterized as an enzyme-responsive drug delivery vehicle. The drug DOX is conjugated to the periphery of dendrimer via an enzyme-responsive tetra-peptide linker Gly-Phe-Leu-Gly (GFLG). The dendrimer-DOX conjugate can self-assemble into nanoparticle, which is confirmed by dynamic light scattering, scanning electron microscopy, and transmission electron microscopy studies. At equal dose, mPEGylated dendrimer-DOX conjugate-based nanoparticle results in significantly high antitumor activity, and induces apoptosis on the 4T1 breast tumor model due to the evidences from tumor growth curves, an immunohistochemical analysis, and a histological assessment. The in vivo toxicity evaluation demonstrates that nanoparticle substantially avoids DOX-related toxicities and presents good biosafety without obvious side effects to normal organs of both tumor-bearing and healthy mice as measured by body weight shift, blood routine test, and a histological analysis. Thus, the mPEGylated peptide dendrimer-DOX conjugate-based nanoparticle may be a potential nanoscale drug delivery vehicle for the breast cancer therapy.

Polymeric nanoparticles have shown great promise as attractive vehicles for drug delivery. In this study, we designed, prepared and characterized biodegradable amphiphilic triblock HPMA copolymer-doxorubicin (copolymer-DOX) conjugate based nanoparticle as enzyme-sensitive drug delivery vehicle. The enzyme-sensitive peptide GFLGKGLFG was introduced to the main chain of the copolymer with hydrophilic and hydrophobic blocks. The triblock HPMA polymer-DOX conjugate with high molecules (Mw 90 kDa) can be degraded to product with low molecule weight (Mw 44 kDa) below the renal threshold. The copolymer-DOX conjugate can self-assemble into compact nanoparticle, which was characterized by scanning electron microscope (SEM) and atomic force microscope (AFM) studies. This polymeric nanoparticle substantially enhanced antitumor efficacy compared to the free DOX, exhibiting much higher effects on inhibiting proliferation and inducing apoptosis on the 4T1 murine breast cancer model confirmed by the evidences from mice weight shifts, tumor growth curves, tumor growth inhibition (TGI), immunohistochemical analysis and histological assessment. The in vivo toxicity evaluation demonstrated that the polymeric nanoparticle reduced DOX-induced toxicities and presented no significant side effects to normal organs of both tumor bearing and healthy mice as measured by body weight shift, blood routine test and histological analysis. Therefore, the triblock HPMA copolymer-DOX conjugate based nanoparticle is promising as a potential drug delivery vehicle for breast cancer therapy.